1. Field of the Invention
The present invention provides a process for producing a 2',3'-dideoxy-2',3'-didehydronucleoside derivative, which is useful as an antiviral agent etc., and intermediates for the production thereof.
2. Discussion of the Background
d4T [1-(2,3-dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine] represented by the formula (XII): ##STR1## is a 2',3'-dideoxy-2',3'-didehydro nucleoside derivative, and has antiviral activity both in vitro and in vivo. Especially, its anti-HIV activity is equivalent to AZT (3'-azido-3'-deoxy-thymidine) which is the first drug that has been approved in USA for the treatment of HIV infection. As regards anti-HIV activity, see M. M. Mansuri et al., Antimicrob. Agents Chemother., 34(4), 637-41 (1990); Y. Hamamoto et al., Antimicrob. Agents Chemother., 31(6), 907-910 (1987); and M. Baba et al., Biochem. Biophys. Res. Commun., 142(1), 128-34 (1987). As regards, anti-HBV activity, see E. Matthes et al., Antimicrob. Agents. Chemother., 34(10) , 1986-90 (1990).
As for the production of d4T from thymidine as a raw material, there are known a process via an oxetane analogue (J. C. Martin et al., Nucleosides Nucleotides, 8(5-6), 841-4 (1988), and M. M. Mansuri et al., J. Med. Chem., 32(2) 461-6 (1989)) , and a process using selenium oxidation (M. J. Vial et al., Nucleosides Nucleotides, 9(2) 245-58 (1990)) . Also is known a process using glycosylation reaction (L. J. Willson et al., Tetrahedron Lett., 31 (13), 1815, (1990), and C. K. Chu et al., J. Org. Chem., 55(5) 1418-20 (1990)). Every process has, however, disadvantageous aspects such as expensiveness of thymidine as a raw material, use of reagents difficult of commercial handling (poisonous or dangerous), difficulty in obtaining d4T in high yields, and the like. As for the synthesis of d4T from 5-methyluridine, processes utilizing radical reduction (C. K. Chu et al., J. Org. Chem., 54(9), 2217-25 (1989), and M. M. Mansuri et al., J. Org. Chem., 54(20), 4780 (1989),) are known. They are, however, not commercially favorable in reagents employed, reaction condition, etc.
In 1974, Marumoto et al. developed a process for the synthesis of 2'-deoxy-2'-bromo-3',5'-O-diacetyluridine represented by the formula (XIII): ##STR2## by reacting uridine with acetyl bromide (AcBr). See Chem. Pharm. bull., 22(1) 128-34 (1974).
Mansuri et al. applied the above process per se to 5methyluridine represented by the formula (XIV): ##STR3## and, by reacting 5-methyluridine with AcBr, synthesized 2'-deoxy-2'-bromo-3',5'-O-diacetyl-5-methyluridine represented by the formula (XV): ##STR4## The resultant compound of the formula (XV) is then reacted with zinc-copper couple (hereinafter, abbreviated as Zn-Cu) to give the corresponding olefin. Thus, the synthesis of d4T was completed. See M. M. Mansuri et al., J. Org. Chem., 54(20), 4780(1989).
On the other hand, the present inventors had studied, prior to Mansuri et al, synthesis of 2'-deoxy-2'-bromo-3',5'-O-diacetyl-5-methyluridine of the formula (XV) by reacting 5-methyluridine with AcBr as an advantageous commercial synthetic process of d4T from 5-methyluridine. Reaction conditions were studied extensively, and it was found that yields are low, and many by-products are produced.
Furthermore, they had also studied .beta.-elimination of 2'-deoxy-2'-bromo-3',5'-O-diacetyl-5-methyluridine into the olefin and found various serious problems in known methods, such as unstableness of Zn-Cu, too much required amounts of Zn-Cu, low reaction yield, required complicated removal procedures of the Zn salt after the reaction (removal procedures in combination of resin purification using a chelate resin or an ion-exchange resin and filtration using celite, etc.), and so on.